Mitigation of aircraft noise-induced vascular dysfunction and oxidative stress by exercise, fasting, and pharmacological α1AMPK activation: molecular proof of a protective key role of endothelial α1AMPK against environmental noise exposure

Abstract

Aims Environmental stressors such as traffic noise represent a global threat, accounting for 1.6 million healthy life years lost annually in Western Europe. Therefore, the noise-associated health side effects must be effectively prevented or mitigated. Non-pharmacological interventions such as physical activity or a balanced healthy diet are effective due to the activation of the adenosine monophosphate-activated protein kinase (α1AMPK). Here, we investigated for the first time in a murine model of aircraft noise-induced vascular dysfunction the potential protective role of α1AMPK activated via exercise, intermittent fasting, and pharmacological treatment. Methods and results Wild-type (B6.Cg-Tg(Cdh5-cre)7Mlia/J) mice were exposed to aircraft noise [maximum sound pressure level of 85 dB(A), average sound pressure level of 72 dB(A)] for the last 4 days. The α1AMPK was stimulated by different protocols, including 5-aminoimidazole-4-carboxamide riboside application, voluntary exercise, and intermittent fasting. Four days of aircraft noise exposure produced significant endothelial dysfunction in wild-type mice aorta, mesenteric arteries, and retinal arterioles. This was associated with increased vascular oxidative stress and asymmetric dimethylarginine formation. The α1AMPK activation with all three approaches prevented endothelial dysfunction and vascular oxidative stress development, which was supported by RNA sequencing data. Endothelium-specific α1AMPK knockout markedly aggravated noise-induced vascular damage and caused a loss of mitigation effects by exercise or intermittent fasting. Conclusion Our results demonstrate that endothelial-specific α1AMPK activation by pharmacological stimulation, exercise, and intermittent fasting effectively mitigates noise-induced cardiovascular damage. Future population-based studies need to clinically prove the concept of exercise/fasting-mediated mitigation of transportation noise-associated disease.

Transportation Noise Pollution and Cardiovascular Health

“…Notably, the absence of endothelium-specific α1AMPK worsened noise-induced vascular damage and nullified the positive effects of exercise or intermittent fasting. 121 These outcomes substantiate that activating endotheliumspecific α1AMPK through pharmaceutical stimulation, exercise, and intermittent fasting effectively mitigates noise-induced cardiovascular damage. The interventions all restored noise exposure-induced blood pressure elevation to the level of unexposed control.…”

“…activation through exercise, intermittent fasting, and pharmacological activation by 5-aminoimidazole-4-carboxamide riboside in a murine model of vascular dysfunction-induced aircraft noise. 121 Mice were subjected to aircraft noise exposure, significantly impairing endothelial function in the aorta, mesenteric arteries, and retinal arterioles. This dysfunction was accompanied by an elevation in vascular oxidative stress and the formation of asymmetrical dimethylarginine.…”

“…phosphate oxidase subunit 2) expression/activation and oxidative stress, in part by cross-activation of NRF2 (nuclear factor erythroid 2-related factor 2) via specific phosphorylation and subsequent HO-1 (heme oxygenase-1) induction followed by carbon monoxide (CO) and bilirubin (BR) production. Adapted from Kvandova et al121 with permission. Copyright ©2023, European Society of Cardiology.…”

Health position paper and redox perspectives - Disease burden by transportation noise

“…Additive increase by noise/AT-II infusion and prevention by LysM + cell ablation and suppression by exercise, fasting and AICAR (AMPK activator). +++ Aorta and brain [ 16 , 245 , 567 ]; Aorta and cardiac mitochondria [ 245 , 247 , 248 , 281 , 567 ] Oxidative burst Whole blood leukocyte-dependent ROS (O 2 •− and H 2 O 2 ) formation upon stimulation with phorbol ester dibutyrate or zymosan A by the luminol analog L-012-enhanced chemiluminescence. Signal abolished in Nox2 knockout mice and was aggravated in Ogg1 knockout mice with impaired repair capacity of 8-OH-(d)G lesions.…”

“…Studies have also found protective effects of NRF-2 activators against mental stress conditions [ 565 ], reflected by the beneficial action of CDDO-imidazole in a model of noise-induced hearing loss [ 566 ]. Of great interest are non-pharmacological mitigation strategies against noise-induced damage (e.g., physical exercise and intermittent fasting), conferring potent antioxidant and anti-inflammatory effects largely mediated by AMPK as shown for noise-exposed mice [ 567 ]. Of note, there is an important connection between NRF-2 and AMPK as the kinase phosphorylates NRF-2 and thereby causes activation of the transcription factor [ 568 ], also with high relevance for the protective effects of physical exercise [ 569 ] and intermittent fasting [ 570 ].…”